According to UNAIDS, about 33.3 million people were living with human immunodeficiency virus (HIV) at the end of 2009, up from 26.2 million people in 1999. HIV is the etiological agent of acquired immunodeficiency syndrome, AIDS. Since the beginning of the epidemic, more than 60 million people have been infected with HIV and nearly 30 million people have died of HIV-related causes. In an effort to decrease the morbidity and mortality associated with HIV infection, a variety of pharmacological interventions have been proposed.
On Mar. 20, 1987, the FDA approved the use of the compound, AZT (zidovudine), to treat AIDS patients who present with an initial episode of Pneumocystis carinii pneumonia, AIDS patients with conditions other than Pneumocystis carinii pneumonia or patients infected with the virus with an absolute CD4 lymphocyte count of less than 200/mm3 in the peripheral blood. AZT is a known inhibitor of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication. U.S. Pat. No. 4,724,232 claims a method of treating humans suffering from AIDS utilizing AZT.
As disclosed in U.S. Pat. No. 6,043,248, certain antibiotics and polyanionic dyes inhibit retroviral reverse transcriptase (an enzyme necessary for HIV replication). In addition, publications have reported the ability of various sulfated compounds to inhibit virus replication, including HIV. The use of benzodiazepine derivatives have been described as being potent and selective inhibitors of HIV replications. See Pauwels et al. (1990) Nature 343:470-474 and Merluzzi et al. (199) Science 250:1411-1413.
Building on some of these early attempts (such as 2′,3′ dideoxynucleoside analogues such as AZT) to address HIV infection, much effort has been focused providing superior agents. In the case of 2′,3′-dideoxynucleosides, ddC and ddI have shown potent activity against HIV in vitro and have been evaluated in clinical trials. See Drug News & Perspectives 5(3):153-169 (1992). Based on this further research, the FDA has approved ddI for the treatment of HIV-1 infections in adults and pediatrics patients who are intolerant to, or whose health has significantly deteriorated while on, AZT treatment.
Additional research has lead to the discovery of non-nucleoside reverse transcriptase inhibitors (or NNRTIs). Like the nucleoside analogs, NNRTIs block HIV's infection of via inhibiting reverse transcriptase. Combination treatment using both a nucleoside analog drug (AZT, ddI, ddC, d4T and 3TC) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are commonly used.
Despite the success experiences with some of these pharmacologic interventions, challenges remain. For example, it is known that HIV develops resistance to many drugs (some in as few as two to seven weeks when the drug is used alone). Thus, there remains a need to provide additional drugs to treat individuals infected with HIV.
Delavirdine, a diaromatic substituted compound is an approved NNRTI that has been in a number of clinical trials. Its efficacy is lower than other NNRTIs, and it also has an inconvenient schedule. The risk of cross-resistance across the NNRTI class, as well as its complex set of drug interactions, make delavirdine and other NNRTIs less suitable as therapy for HIV patients. The most common adverse event is moderate to severe rash, which occurs in up to 20% of patients. Other common adverse events include fatigue, headache and nausea. Liver toxicity has also been reported.
Therefore, pharmacotherapy with such therapeutic diaromatic substituted compounds would be improved if these and/or other adverse or side effects associated with their use could be decreased or if their pharmacology may be improved. Thus, there is a large unmet need for developing novel diaromatic substituted compounds to address not only these concerns, but the concern associated with resistance as well.
The present invention seeks to address these and other needs in the art.